la mikula, pf ridgway, cn catton, jj jones, b o’sullivan, ma ko, cj swallow university of toronto
DESCRIPTION
Long-term follow-up of a prospective trial of pre-operative external-beam radiation and post-operative brachytherapy for retroperitoneal sarcoma. LA Mikula, PF Ridgway, CN Catton, JJ Jones, B O’Sullivan, MA Ko, CJ Swallow University of Toronto - PowerPoint PPT PresentationTRANSCRIPT
Long-term follow-up of a prospective trial of pre-
operativeexternal-beam radiation
and post-operative brachytherapy
for retroperitoneal sarcomaLA Mikula, PF Ridgway, CN Catton, LA Mikula, PF Ridgway, CN Catton, JJ Jones, B O’Sullivan, MA Ko,JJ Jones, B O’Sullivan, MA Ko,
CJ SwallowCJ Swallow
University of TorontoUniversity of TorontoMount Sinai Hospital & Princess Margaret HospitalMount Sinai Hospital & Princess Margaret Hospital
Toronto, CanadaToronto, Canada
Retroperitoneal Sarcoma:Retroperitoneal Sarcoma:the Challengethe Challenge
Retroperitoneal SarcomaRetroperitoneal SarcomaPrincess Margaret HospitalPrincess Margaret Hospitaln=45 resected patients, 1975-n=45 resected patients, 1975-
19881988
0
20
40
60
80
100
perc
enta
ge o
f patie
nts 5 yr
10 yr
OS Local Relapse-
Free Survival
Distant relapse-Free
SurvivalCatton, O’Sullivan et al, Int J Rad Oncol Biol Phys 1994; 29:1005.
Adjuvant RadiationAdjuvant Radiation
Treatment SchemaTreatment Schema Patients with RPS referred to Princess Margaret Patients with RPS referred to Princess Margaret
Hospital, Toronto, June 1996-April 2003Hospital, Toronto, June 1996-April 2003 Inclusion criteria: resectable disease & no Inclusion criteria: resectable disease & no
mestastases; signed informed consentmestastases; signed informed consent
Pre-operative XRT: 45 Gy/5 weeks
4-6 weeks
Surgery
Post-operative brachytherapy (BT):
25 Gy (0.5Gy/hr, depth 0.5cm)
RPSn=83
n=55trial
resectionn=46
metsn=5
pre-op deathn=4
pre-op XRTn=40
BTn=2
BT and post-op XRT n=2
no RTn=2
+ BTn=19
- BTn=21
recent resection
n=14
incurablen=12
refusedtherapy n=2
XRT = external beam radiation therapyBT = post-operative brachytherapy
Jones et al, Ann Surg Onc 2002,9,346
Pre-operative External Pre-operative External Beam RadiationBeam Radiation
Conformal planning using 3D Conformal planning using 3D techniquestechniques
Shielding of contralateral kidney; Shielding of contralateral kidney; liverliver
Post-operative Post-operative BrachytherapyBrachytherapy
Single plane of 3-8 afterloading BT catheters Single plane of 3-8 afterloading BT catheters placed on the surgical bed with 1cm spacingplaced on the surgical bed with 1cm spacing
Planar implant dose of 0.5 Gy/hr, depth Planar implant dose of 0.5 Gy/hr, depth 0.5cm0.5cm
Afterloading iridium-192 pulsed dose rate Afterloading iridium-192 pulsed dose rate BT unitBT unit
BT initiated once GI function returned (7-14 BT initiated once GI function returned (7-14 days post-op)days post-op)
Outcomes & Follow-upOutcomes & Follow-up
Follow-up: clinic visit + CT scan every 6 Follow-up: clinic visit + CT scan every 6 months x5 years, then anuallymonths x5 years, then anually Minimum follow-up 48 monthsMinimum follow-up 48 months
Outcomes:Outcomes: SurvivalSurvival Disease recurrenceDisease recurrence Toxicity: Radiation Therapy Oncology Group Toxicity: Radiation Therapy Oncology Group
scoresscores Pre-operative toxicityPre-operative toxicity Acute post-operative toxicity (within 3 months)Acute post-operative toxicity (within 3 months) Late toxicity (3 months to 1 year post-op)Late toxicity (3 months to 1 year post-op)Jones et al, Ann Surg Onc
2002,9,346
Results: ToxicityResults: Toxicity
Pre-Operative Toxicity:Pre-Operative Toxicity:40 patients treated with 40 patients treated with
pre-op XRTpre-op XRT All patients had a maximum RTOG All patients had a maximum RTOG
score of ≤ 2score of ≤ 2
Acute toxicity scores related to Acute toxicity scores related to upper and lower GI symptoms …upper and lower GI symptoms … … … except for one patient who developed except for one patient who developed
cystitiscystitis
Jones et al, Ann Surg Onc 2002,9,346
Acute Post-operative Acute Post-operative Toxicity:Toxicity:
46 resected patients46 resected patients1
mild 3
hospital admission
4life-
threatening
5death
15 8 5 11 6 1
0none
2medicaltherapy
n=
Hepatic failure
4/6 had BT
Jones et al, Ann Surg Onc 2002,9,346
Modified Late ToxicityModified Late Toxicity(3-12 months post-op)(3-12 months post-op)
1mild
3hospital
admission
4life-
threatening
5death
36 1 1 1 1 2
0none
2medicaltherapy
n=
2 late complicationsof duodenal perforation 6/6 had BT
Jones et al, Ann Surg Onc 2002,9,346
Results:Results:Long-term Long-term Follow-upFollow-up
Clinicopathologic Features:Clinicopathologic Features:Pre-op XRT + SurgeryPre-op XRT + Surgery
N=40N=40 Male 15, female 25Male 15, female 25 Median age 58 yrs (range 41-75)Median age 58 yrs (range 41-75)
Primary presentation of RPS = 29 (72%)Primary presentation of RPS = 29 (72%) Referred with recurrent disease = 11 (28%)Referred with recurrent disease = 11 (28%)
Tumour characteristics:Tumour characteristics: Median size 19cm (range 4-40cm)Median size 19cm (range 4-40cm) 55% high grade55% high grade 70% liposarcoma70% liposarcoma
Liposarcoma
Leiomyosarcoma
MFH
Other
Treatment Treatment CharacteristicsCharacteristics
Patients who completed pre-op XRT & Patients who completed pre-op XRT & surgery:surgery: Median pre-op XRT dose = 45 Gy (range 45-Median pre-op XRT dose = 45 Gy (range 45-
57 Gy)57 Gy) Median BT dose = 23 Gy (range 7.5-25 Gy)Median BT dose = 23 Gy (range 7.5-25 Gy)
All resections were grossly completeAll resections were grossly complete 97% had resection of contiguous structures97% had resection of contiguous structures
No patients received adjunctive chemotherapyNo patients received adjunctive chemotherapy
Status at Last Follow-UpStatus at Last Follow-Up
Median follow-up 89 months (7.4 years)Median follow-up 89 months (7.4 years) No patients lost to follow-upNo patients lost to follow-up
4 patients recurred and were re-resected4 patients recurred and were re-resected
At last follow-up:At last follow-up: 25 alive and disease-free (62.5%)25 alive and disease-free (62.5%) 3 alive with recurrent disease (7.5%)3 alive with recurrent disease (7.5%) 9 dead of disease (22.5%)9 dead of disease (22.5%) 3 dead of other causes (7.5%)3 dead of other causes (7.5%)
Alive, disease-free
Alive, recurred
Dead of disease
Dead of other
5yr OS 10yr OS 75% 63%
median OS not reached at median 89 mos. f/u
(months)
Overall Survival (n=40)
5yr RFS 10yr RFS 69% 52%
median RFS ≈ 120 mos. median 89 mnths f/u
Recurrence-Free Survival (n=40)
Median not reached
5yr OS 10yr OS
80% 80%
Log Rank: p=0.27
median OS not reached
5yr OS 10yr OS
68% 54%
OS BT (n=19) vs no BT (n=21)
5yr RFS: 75% 10yr RFS:--
Log Rank: p=0.58
No BT: median RFS not reached
BT: median RFS ≈ 106 mnths
5yr RFS 10yr RFS 61% 47%
RFS BT (n=19) vs no BT (n=21)
5yr RFS 10yr RFS 68% ---
Log Rank: p=0.68
No BT, n=10
BT, n=12No BT: median OS not reached
BT: median OS ≈ 116 mnths
5yr RFS 10yr RFS 58% 47%
OS in High-Grade Tumours (n=22)
Prospective Trials of Combined Prospective Trials of Combined Radiation + Resection for RPSRadiation + Resection for RPS
Ttl Ttl N=N=
RxRx N=N= OS OS median/median/
5yr (%)5yr (%)
RFS RFS median/median/
5yr (%)5yr (%)
Sindelar Sindelar ’93, NIH ’93, NIH PhIII RCT PhIII RCT ’80-’85’80-’85
3535 PostOp XRT (50-55Gy)PostOp XRT (50-55Gy)
PostOp XRT (35-40Gy) PostOp XRT (35-40Gy) + IORT + misonidazole+ IORT + misonidazole
2020
151552 mos.52 mos.
45 mos.45 mos.
Robertson Robertson ’95, U ’95, U Mich PhIMich PhI
1616 PreOp XRT + IdUrdPreOp XRT + IdUrd
PreOp XRT + IdUrd + PreOp XRT + IdUrd + OROR
55
111118 mos.18 mos.
32 mos.32 mos.
Alektiar Alektiar ’00, ’00, MSKCC MSKCC PhI-II, PhI-II, ’92-’96’92-’96
49-49-17=17=3232
OR + IORT + PostOp OR + IORT + PostOp XRTXRT
OR + IORTOR + IORT
2525
7745%45% 55%55%
Pisters ’03, Pisters ’03, MDA PhI, MDA PhI, ’96-’01’96-’01
3535 Dox + PreOp XRTDox + PreOp XRT
Dox + PreOp XRT + ORDox + PreOp XRT + OR
… … + IORT+ IORT
88
55
2222
Phase I Phase I trialtrial
Mikula ’08, Mikula ’08, Toronto, Toronto, PhI-II, PhI-II, ’96-’00’96-’00
4040 PreOp XRTPreOp XRT
PreOp XRT + BTPreOp XRT + BT2121
191980%80%
68%68%75%75%
61%61%
Historical vs. Current Historical vs. Current DataData
0
20
40
60
80
100
perc
enta
ge o
f patie
nts 5 yr
10 yr
OS Local Relapse-
Free Survival
Catton, O’Sullivan et al, Int J Rad Oncol Biol Phys 1994; 29:1005.
ConclusionsConclusions
Pre-operative XRT was well toleratedPre-operative XRT was well tolerated
Brachytherapy to the upper abdomen Brachytherapy to the upper abdomen was associated with significant toxicitywas associated with significant toxicity
Pre-operative XRT and aggressive Pre-operative XRT and aggressive surgical resection shows promise in surgical resection shows promise in improving local control and long-term improving local control and long-term survival in RPSsurvival in RPS
Intent-to-treat AnalysisIntent-to-treat Analysis
For all 55 patients entered into the trial: For all 55 patients entered into the trial: 2-year OS 73%2-year OS 73%
For 46 patients resected with curative For 46 patients resected with curative intent: 2-year OS 88%intent: 2-year OS 88%